Gene Transfer for Severe Combined Immunodeficiency, X-linked (SCID-X1) Using a Self-inactivating (SIN) Gammaretroviral Vector
Phase: Phase 1/Phase 2
DFCI Protocol ID:
Researchers are working on ways to treat SCID patients who don't have a matched brother or sister. One of the goals is to avoid the problems that happen with stem cell transplant from parents and unrelated people, such as repeat transplants, incomplete cure of the immune system, exposure to chemotherapy, and graft versus host disease. The idea behind gene transfer is to replace the broken gene by putting a piece of genetic material (DNA) that has the normal gene into the child's cells. Gene transfer can only be done if we know which gene is missing or broken in the patient. For SCID-X1, gene transfer has been done in the laboratory and in two previous clinical trials by inserting the normal gene into stem cells from bone marrow. The bone marrow is the "factory" inside the bones that creates blood and immune cells. So fixing the gene in the bone marrow stem cells should fix the immune problem, without giving chemotherapy and without risk of graft versus host disease, because the child's own cells are used, rather than another person's. Out of the 20 subjects enrolled in the two previous trials, 18 are alive with better immune systems after gene transfer. Two of the surviving subjects received gene corrected cells over 10 years ago. Gene transfer is still research for two reasons. One is that not enough children have been studied to tell if the procedure is consistently successful. Of the 20 children enrolled in the previous two trials, one child did not have correction of the immune system, and died of complications after undergoing stem cell transplant. The second important reason why gene transfer is research is that we are still learning about the side effects of gene transfer and how to do gene transfer safely. In the last two trials, 5 children have experienced a serious side effect. These children developed leukemia related to the gene transfer itself. Leukemia is a cancer of the white blood cells, a condition where a few white blood cells grow out of control. Of these children, 4 of the 5 have received chemotherapy (medication to treat cancer) and are currently in remission (no leukemia can be found by sensitive testing), whereas one died of gene transfer-related leukemia.
Children's Hospital Boston, Dana-Farber Cancer Institute
Luigi Notarangelo, MD,
Children's Hospital Boston
Dana-Farber Cancer Institute:
Childrens Hospital Pediatric Clinical Translation Investigation Program CTIP, email@example.com
1. Diagnosis of SCID-X1 based on immunophenotype (<200 CD3+ autologous T cells, and
confirmed by DNA sequencing)
2. Lack an HLA identical (A, B, C, DR, DQ) related donor
AND either one of the following:
1. Patients in good clinical condition who do not have a readily available HLA identical
(A,B,C,DR,DQ) unrelated donor (readily available defined as: a donor confirmed within 6
weeks of searching, with ability to transplant within 3 months of diagnosis).
2. Patients with an active, therapy-resistant infection or other medical conditions that
significantly increase the risk of allogeneic transplant. Examples of "therapy-resistant
infections that significantly increase the risk of allogeneic transplant" include but are
not limited to:
1. interstitial pneumonia due to adenovirus or parainfluenzae virus.
2. protracted diarrhea requiring total parenteral nutrition.
3. disseminated BCG infection.
4. virus-induced lymphoproliferative disease.
5. any active opportunistic infection (eg, due to Pneumocystis jiroveci,
cytomegalovirus,cryptosporidium) that does not improve on medical management.
6. active and progressive pulmonary disease requiring mechanic ventilation. Inclusion of
patients with disease-related organ dysfunction is justified by the known poor
outcome with standard treatment and the potential life-saving nature of the treatment
proposed. Patients who are on high-dose steroids or other immunosuppressive agents
will also be considered eligible, because use of these drugs is common in patients
with SCID and maternal T cell engraftment or who present with severe interstitial
lung disease. Use of immunosuppressive drugs does not affect efficacy of
hematopoietic cell transplantation, and therefore should not affect efficacy of gene
1. No available molecular diagnosis confirming SCID-X1.
2. Patients who have an available HLA-identical related donor.
3. Diagnosis of active malignant disease other than EBV-associated lymphoproliferative
4. Patients with evidence of infection with HIV-1
5. Previous gene transfer
6. Major (life-threatening) congenital anomalies. Examples of "major (life-threatening)
congenital anomalies" include, but are not limited to: unrepaired cyanotic heart
disease, hypoplastic lungs, anencephaly or other major CNS malformations, other
severe non-repairable malformations of the gastrointestinal or genitourinary tracts
that significantly impair organ function.
7. Other conditions which in the opinion of the P.I. or co-investigators,
contra-indicate collection and/or infusion of transduced cells or indicate patient's
inability to follow the protocol. These may include for example clinical
ineligibility to receive anesthesia, severe deterioration of clinical condition of
the patient after collection of bone marrow but before infusion of transduced cells,
or documented refusal or inability of the family to return for scheduled visits.
There may be other unforeseen rare circumstances that would result in exclusion of
the patient, such as sudden loss of legal guardianship.
Although the presentation of the disease may be variable in type, the severity of the
immunodeficiency is uniform. The gene transfer protocol will be instituted in the place of
haploidentical transplant for those patients who do not have a matched family donor or in
whom an unrelated donor transplant is not indicated for the reasons specified above. Apart
from the gene transfer protocol, the patients will not undergo additional procedures that
would not form part of an equivalent haploidentical transplantation regimen, and will not
receive conditioning chemotherapy.